After a wide variety of spinal cord injuries (SCI), humans and animals can recover a greater level of functional stepping if they are given appropriate use-dependent step training. Following complete SCI, substantial reorganization of sensorimotor pathways occurs caudal to the lesion. Step training significantly influences this reorganization. Behavioral and physiological effects of SCI and step training are reflected in adaptations in most, if not all, intrinsic spinal neurotransmitter systems. Previous studies in this program have characterized extensive neuromuscular plasticity following complete SCI. Little is known about the potential for interactions of intrinsic spinal systems involved in neuromuscular plasticity with descending axons that are spared after partial SCI or are regenerating after experimental interventions. The present study will examine the contribution of different descending spinal pathways to the control of stepping and determine how lesions of different pathways influence neuromuscular plasticity after SCI and step training. Understanding which descending spinal pathways are important for control of specific aspects of hindlimb movement, and which pathways should be particularly targeted for regeneration, would represent an important advance. In addition, we will study the effects of partial axon regeneration achieved after transgenically targeted ablation of scar forming, reactive astrocytes. We hypothesize that partial regeneration of descending pathways will interact synergistically with the spinal neuromuscular plasticity that is induced by step training and will augment control of stepping after SCI. These studies will take advantage of recently developed, robot-assisted evaluation of stepping, and combine this with video analysis and electromyographic recordings in adult transgenic mice. Mice will be used as experimental animals because transgenic technology in mice provides a powerful means for precise cellular and molecular manipulations whose effects can be evaluated at the systems level in vivo. This technology holds considerable promise for dissecting out specific molecular and cellular mechanisms after SCI. Results from the present study will establish a framework for quantitative evaluation of the neuromuscular control of stepping in mice, and will provide important information about (i) how lesions of different spinal pathways influence neuromuscular plasticity and the control of stepping, (ii) how partial axon regeneration may improve this control, and (iii) how step training augments these processes.